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Microsomal cytochrome P-452 induction and peroxisome proliferation by hypolipidaemic agents in rat liver

1988; Elsevier BV; Volume: 37; Issue: 7 Linguagem: Inglês

10.1016/0006-2952(88)90770-8

1873-2968

Raj Kumar Sharma, Brian G. Lake, John R. Foster, G. Gordon Gibson,

Pharmacogenetics and Drug Metabolism

Eight structurally diverse hypolipidaemic agents have been examined for their ability to induce the microsomal cytochrome P-452-dependent fatty acid hydroxylase system and the enzymes of peroxisomal β-oxidation in rat liver. Using a specific ELISA method, we have shown that the cytochrome P-452 isoenzyme is induced up to ten fold by hypolipidaemic challenge, concomitant with a pronounced elevation of the peroxisomal β-oxidation enzymes, mirrored by an increase in peroxisomal volume as determined morphometrically. In addition, the induction of cytochrome P-452 is accompanied by a decrease in the activities of cytochromes P-450b and P-450c as measured by benzphetamine N-demethylase and ethoxyresorufin O-deethylase activities respectively, the latter being more extensively reduced by hypolipidaemic treatment. A hypothesis is presented whereby an early biological response is the hypolipidaemic induction of microsomal cytochrome P-452 resulting in ω-hydroxy fatty acids and their subsequent further oxidation to dicarboxylic acids, the latter providing the proximal stimulus for peroxisomal proliferation.